The use of complimentary and alternative medicine approaches is getting increasing popularity with patients of prostate cancer (CaP) that is the most common type of cancer in American men. In several clinical studies, melatonin (N-Acetyl-5-methoxytryptamine), a direct free radical scavenger and an antioxidant, has shown promise, either alone or in combination with traditional therapy, for the management of cancer. In vitro cell culture studies have indicated that melatonin possesses antiproliferative effects against human CaP cells. In our preliminary studies, we found that melatonin-treatment resulted in significant growth inhibition and a Gl-phase cell cycle arrest in both androgen-responsive LNCaP and androgen-unresponsive DU145 cells. Further, melatonin treatment to LNCaP cells resulted in a significant i) activation of its receptor MEL la, ii) decrease in the phosphorylation of mitogen activated protein kinase (MAPK), iii) decrease in the phosphorylation of mitogen activated protein kinase (MAPK), and iv) decrease in prostate specific antigen (PSA). Studies have shown the activation of melatonin-receptor modulates MAPK-pathway via suppression of cAMP that leads to a suppression of linoleic acid (LA) tumor uptake. This proposal capitalizes on these novel observations and the central hypothesis of the work proposed in this application is that melatonin will inhibit prostate cancer via melatonin-receptor mediated modulations in lipoxygenase-15- MAPK signaling. Employing a series of human CaP cells and normal human prostate cells, we will first assess the effect of melatonin on i) melatonin receptor, ii) 15-lipoxygenase and related events, and ii) MAPK-pathway, during its anti-proliferative/pro-apoptotic effects. Next, to validate the outcome of in vitro studies to in vivo situations, we will assess the anti-cancer effects of melatonin on prostate cancer development and its metastasis, employing transgenic adenocarcinoma mouse prostate (TRAMP) model that closely mimics human disease. The major advantage of this model is that metastatic CaP, in these animals, develops spontaneously without any chemical or hormonal treatment. The effect of melatonin-treatment will be evaluated on CaP development via monitoring tumor growth, tumor weight, volume and characteristics at the termination of the experiment. The effect of melatonin on CaP-metastasis will also be assessed. This will establish the anti-cancer effects of melatonin against CaP. We believe that a successful completion of this proposal will define i) the potential of melatonin against CaP, and ii) molecular mechanism(s) of the biological effects of melatonin.